JPS5842852B2 - Method for producing 2-(4'-isobutylphenyl)propionic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 2-(,4'-inbutylphenyl)propionic acid.

2-(4'-isobutylphenyl)propionic acid (common name ibuprofen) is a compound useful in medicine, particularly as an anti-inflammatory analgesic.

Conventional methods for producing 2-(4'-isobutylphenyl)propionic acid include, for example, Japanese Patent Publication No. 22297, No. 43, No. 18105, No. 47-2, No. 47-2.
4550, JP-A-47-390501 JP-A-49-95
936, JP 49-93937, JP 49-108
040, JP 1973-133351, JP 50-4040, JP 50-4
0541, JP 50-41830, JP 50-13
5049, JP-A-51-23235, JP-A-51-54
Although many synthesis methods have been proposed, such as No. 527 and JP-A No. 51-54531, they are not necessarily fully satisfactory industrial production methods.

As a result of various studies, the present inventor discovered a method for producing 2(4'-isobutylphenyl)propionic acid** in good yield by a novel synthetic route different from conventionally known production methods, and completed the present invention. .

That is, the present invention is carried out by a novel synthetic route shown in the following formula (A).

The intermediate compounds (I), (III), and (IV) in the present invention are all novel compounds unknown in the literature, and were synthesized by the present inventor, and their physical properties were clarified as described in the Examples. .

Intermediate (IV) in the first step of the present invention can be easily obtained by reacting raw material 4-isobutylphenylacetonitrile (■) with acetic acid ester in the presence of a condensing agent.

As the condensing agent, an alkali metal lower alcoholade such as sodium ethylate or sodium isopropylade is preferably used.

The reaction was carried out under mild conditions at 50 to 90°C using alcohol as a solvent, and 2-aceto-2-(
4/-isobutylphenyl)acetonitrile (IV) is obtained.

2-ace)-2-(4'-isobutylphenyl)propionitrile (III) in the second step of the present invention is 2-ace)-
2-(4'-isobutylphenyl)acetonitrile (I
It can be easily obtained by reacting V) with a methylating agent.

Examples of the methylating agent include dimethyl sulfate, methyl iodide, methyl bromide, methyl fluorosulfonate, and trimethyl phosphate, among which dimethyl sulfate is economically advantageous.

Methylation proceeds easily under mild conditions in the presence of an alkali, and 2-aceto-2-(4'-isobutylphenyl)propionitrile (III) is obtained in good yield.

In this reaction, an organic solvent inert to the reaction system can be selected as appropriate, and lower alcohols are particularly preferably used.

Examples include evaporated methyl alcohol, ethyl alcohol and isopropyl alcohol.

Alcolade, an alkali metal, is used as an alkali agent in methylation, but in the present invention, acidic soda or potassium can be used to achieve a good yield without using such expensive chemicals that require careful handling. Methylation can be achieved at a high rate.

One feature of the present invention is that the intermediate 2-aceto2-(4'-inbutylphenyl)acetonitrile (IV) can be isolated as an air-stable sodium salt crystal.

The sodium salt of 2-aceto-2-(4'-isobutylphenyl)acetonitrile can be prepared by mixing 2-aceto-2=(4'-isobutylphenyl)acetonitrile (■) in the above-mentioned lower alcohol, such as ethyl or impropyl alcohol. Although it can be easily obtained by stirring the same mole of sodium hydroxide at a temperature below room temperature, in the first step, in the first step, acetic acid ester is added to 4-isobutylphenylacetonitrile (V) and a lower alcohol is added. 2- by condensation in the presence of alcolade in
The alkali metal salt of aceto-2-(4'-isobutylphenyl)acetonitrile (IV), such as the sodium salt, precipitates as crystals and can be easily isolated by filtration if necessary.

Therefore, the sodium salt of the compound **(■) obtained here can be used as it is in the methylation reaction in the third step, so one of the advantages of the method of the present invention is that there is no need for a separate production operation of the alkali salt. It is one.

Furthermore, in the first step, the present invention introduces an acetyl group into 4-isobutylphenylacetonitrile (■) to produce 2-aceto-2-(4'-isobutylphenyl)acetonitrile (IV), thereby improving the process compared to conventionally known methods. It has the following features and advantages:

As a conventional method for producing 2-(4/-furkylphenyl)propionic acid, the route represented by the following formula [B] is known.

(R represents an alkyl group) However, in the method according to the route of formula 33 above, special reaction conditions are required for methylation of 4-alkylphenylacetonitrile, and good results are not necessarily obtained in terms of yield.

For example, in a known method that uses soda amide as a condensing agent for the methylation reaction, the temperature is extremely low (-78°C) in liquid ammonia.
The disadvantage is that it requires multiple operations, making it unsuitable for industrial mass production.

In addition, methods using extremely strong reagents such as sodium hydride as condensing agents are also known, but even in this case, methyl iodide and methyl bromide, which have low boiling points, are difficult to handle, and are expensive. These known methods are difficult and dangerous, and also have drawbacks such as the formation of dimethylated side-reactants.

Therefore, as a way to avoid these drawbacks, the current method is to use an alkylphenylmalonic acid diethyl ester derivative, and this fact proves the difficulty of methylating 4-phenylacetonitrile. There is.

However, in the method of the present invention, 2-aceto-2-(4'-isobutylphenyl) obtained by introducing an acetyl group into 4-isobutylphenylacetonitrile (V)
As mentioned above, acetonitrile (IV) can not only be isolated as an alkali salt crystal that is stable in the atmosphere, but also can be easily isolated in high yield using an industrial methylating agent such as dimethyl sulfate at room temperature or under mild conditions close to it. It has the advantage of being methylated.

Furthermore, another advantage of the method of the present invention is that the known CB
) The starting compound, 4-alkylphenyl acetonitrile, is usually produced industrially by an advantageous manufacturing method in which alkylbenzyl chloride is synthesized by the so-called Groskinski reaction in which formalin, hydrochloric acid, and zinc chloride are reacted on alkylbenzene, and then nitrification is performed. However, a drawback of this production route is that even if appropriate conditions are selected for chloromethylation, in addition to para-substituted products, around 10% of ortho-substituted products are inevitably produced as by-products.

Moreover, since the boiling points of both isomers are similar, it is industrially difficult to separate the para-isomer with high purity.

Even if the chloromethyl isomer is nitrified, the difference in boiling point between the two isomers is not large, so it is industrially difficult to obtain a highly pure para isomer even in the nitrile form.

However, when using the method of the present invention, as described above during the production of 2-ace)-2-(4'isobutylphenyl)acetonitrile (IV) in the first step, an alkali metal salt of (IV), such as a sodium salt, is added. We found that it can be isolated as a stable crystal in the atmosphere.

Therefore, by isolating this sodium salt, if the starting compound (V) contains an orthoisomer, the sodium salt of the orthoiso*heptamer of compound (IV) that would be produced is Because it is difficult to crystallize, the orthoisomer is removed by washing with an appropriate solvent and eluted into the filtrate, yielding a highly purified sodium salt of 2-ace)-2-(4/-isobutylphenyl)acetonitrile (IV). discovered the unexpected benefit of being able to

Furthermore, one of the advantages of the present invention is that the introduction of an acetyl group into 4-isobutylphenylacetonitrile (V) in the first step is carried out using acetic acid ester, which is a raw material chemical that can be obtained industrially at low cost. Here are some possible points.

In the following reaction route formula (C), which is a known method using a conventional arylmalonic acid diethyl ester derivative, the nitrile is first converted into phenylacetic acid, esterified, and further condensed with expensive diethyl carbonate, and then methylated. The ester is then hydrolyzed and then thermally decomposed, and this method requires two steps using sodium alcoholade as a condensing agent.

Compared to this method, the method of the present invention has shorter steps as described above, requires only one step of condensation with sodium alcoholade, and is economically advantageous because acetic acid ester, which is cheaper than diethyl carbonate, can be used. can.

Next, the third step of the present invention is to hydrolyze 2-aceto-2(4'-isobutylphenyl)propionitrile (II[) to produce 2-aceto-2-(4'-isobutylphenyl).
Propionamide (I) is obtained in the step of al.

As the hydrolyzing agent, an acid or an alkali can be used, but good results are preferably obtained by using dilute sulfuric acid, especially dilute sulfuric acid with a concentration of 60 to 85%.

The reaction proceeds easily at a temperature of 50 to 90°C.

In addition to dilute sulfuric acid, an aqueous solution of hydrochloric acid, phosphoric acid, sodium phosphate, sodium acetate, or acetic alkali at an appropriate concentration or a mixed solvent of an organic solvent and water can also be used. It is carried out using a certain solvent and selecting appropriate temperature conditions.

However, dilute sulfuric acid is the most economical and advantageous. 2 from reactant
-Ace)-2-(4'-isobutylphenyl)propionamide (■) can be isolated by discharging the reaction solution into water, for example, when hydrolyzed with dilute sulfuric acid. Since (4/-inbutylphenyl)propionamide (I) precipitates as crystals, it can be easily isolated by removing the fraction after one filtration.

The compound (I) obtained here can be used as it is in the next step, but if necessary, it can be made to a higher purity by recrystallizing it from a suitable solvent, for example n-hexane.

Note that 2-ace)-2-(4'-isobutylphenyl)propionamide (I) obtained here is also a new compound unknown in the literature.

Next, in the fourth step of the present invention, 2-aceto-2-(4'-isobutylphenyl)propionamide (I) is hydrolyzed to obtain the desired 2(4/-isobutylphenyl)propionic acid (n). This is the process of obtaining

Hydrolysis in this step can be carried out using acid or alkali as in the previous step, but good results can be obtained preferably by heating in an organic solvent containing hydrochloric acid.

Examples of the solvent in this case include acetic acid, but it is also possible to appropriately select a solvent other than acidic and acetic acid that is inert to the reaction system.

The reaction temperature progresses easily between room temperature and 110'C.

From the reactant to the desired 2(4/-inbutylphenyl→
To isolate propionic acid (I[), after the reaction is complete, remove the solvent from the reaction solution if necessary, such as acetic acid, by distilling most of it under reduced pressure, and drain the residue into water. By doing so, 2-(4'-isobutylphenyl)propionic acid (n) precipitates as crystals, which can be easily isolated by filtering.

The crystals obtained here may be treated with a suitable solvent, for example n
- Recrystallization using hexane, acetone, ethyl acetate, etc. will yield a product with even higher purity.

Alternatively, the crude crystals are eluted with dilute alkaline water, such as a 10% sodium carbonate aqueous solution, and if there is an insoluble part [mainly unreacted compounds (■)], it is separated, and the soluble part is acidified with dilute hydrochloric acid to precipitate crystals. A highly pure product can also be easily isolated by a method in which the product is filtered through one pass.

In carrying out the present invention, the operation of isolating 2-aceto-2-(4'-isobutylphenyl)propionamide (n) produced in the third step is omitted, and the hydrolysis reaction in the fourth step is then carried out. It is also possible to do this.

In this case, hydrolysis can be carried out in the presence of an alkali in a dilute acetic acid containing dilute sulfuric acid or hydrochloric acid, or an inert solvent having an affinity for water, under appropriate conditions.

4-isobutylphenylacetonitrile, which is the starting material of the present invention, can be produced industrially advantageously by the Groskinski reaction of alkylbenzene and the reaction of the resulting alkylbenzyl chloride with sodium hydroxide, but there are some Ortho form by-products are inevitable (see reference side).

However, according to the method of the present invention, these can be easily separated.

The method of the present invention will be specifically explained below with reference to Examples.

Example 1 Preparation of 2-7ce)-2-(4'-isobutylphenyl)acetonitrile (IV) In a flask equipped with a stirrer, a dropping funnel, a thermometer and a reflux condenser, 65 TrL of absolute ethyl alcohol,
3.5 f (0,152 mol) of metallic sodium was added and stirred to prepare sodium ethylate.

Next, 4-isobutylphenylacetonitrile 20S' (
0,116 mol) and ethyl acetate 181 (0,205 mol)
75 to 80 mol) into a dropping funnel and mix well.
The mixture was added dropwise into the flask over a period of 1.5 hours at ℃.

After the addition, the mixture was stirred at room temperature for 2 hours. Then, most of the ethyl alcohol was recovered under reduced pressure, and the residue was poured into 200 TfL of water.
The undissolved oil was removed by extraction and separation with benzene.

While cooling, acetic acid was added to the aqueous solution to make it acidic (PH4), and the precipitated oil was extracted and separated with benzene, washed with water, dried over anhydrous sulfur salt, and distilled under reduced pressure to obtain 2-aceto-2-(4'-isobutyl). Phenyl)acetonitrile (■) was obtained.

Boiling point: 117-b Yield: 71.2% (based on 4-inbutylphenylacetonitrile).

IR; (Liquid film νcIIL-1); 3000-3400.
2800-300012200, 1730.16401
1510.1465.1350.1180.850.8
00゜Elemental analysis result CHN Analysis value (%) 78.34 7.95 6.26 Calculated value (%) 78.14 7.90 6.51 (C14
H1□No) Example 2 Production of 2-ace)-2-(4'-isobutylphenyl)propionitrile (■) Into the same reaction flask as described in Example 1, 50% of ethyl alcohol was added.
0 TrLl, 2 ml of water and 1.41 (0,0
25 mol) and stirred to dissolve.

2 obtained in Example 1 was placed in this while cooling with ice water from the outside.
-ace)-2-(4'-isobutylphenyl)acetonitrile (IV) 5.01 (0,023 mol) was gradually added and stirred well.

Next, in this, 3.4f (0,027 mol) of dimethyl sulfate
was added dropwise at 10° C. over a period of 1 hour.

After stirring at 5 to 10°C for 2 hours, the temperature was gradually raised and stirring was continued at room temperature for 3 hours to complete the reaction.

The solvent ethyl alcohol was then recovered under reduced pressure.

Add 100rrLl of water to the residue, extract the precipitated oil with benzene, separate the liquids, wash with water, dry over anhydrous salt water, and distill under reduced pressure to obtain 2-aceto-2-(4'-isobutylphenyl)propionitrile (III). ) was obtained.

Boiling point 123-125℃/1.511L711Hg, yield 4.81゜Yield 9o, 2% [vs. 2-acetate], -2-(4
'-isobutylphenyl)acetonitrile].

IR; (Liquid film νCrrL-1): 3000-2800.
2240, 1730, 151011460.1360,
1185 1095 1023855, 800° Elemental analysis result CNN Analysis value (%) 78.82 8.34 6.17 Calculated value (%) 78.60 8.29 6.11 (C15
Example 3 Production of 2-aceto-2-(4'-isobutylphenyl)propionamide (■) Into the same reaction flask as described in Example 1, 24rrLl of 84% dilute sulfuric acid was added while stirring. 2-ace)-2-(4'-isobutylphenyl)propionitrile (III) obtained in Example 2 from the dropping funnel2. Of(0,008
mol) was gradually added dropwise over a period of 30 minutes at 3 to 10°C.

After stirring at the same temperature for 1 hour, gradually raise the temperature to 68-7
Stir at 0°C for 2 hours.

After cooling, the reaction product was discharged into 200 TrL of ice water, thoroughly stirred, and left to stand, and the oily substance eventually became crystals.

The crystals were extracted with benzene, the benzene was distilled off, and the resulting crude crystals were recrystallized from n-hexane to give 2-aceto-
2-(4'-isobutylphenyl)propionamide (
I) was obtained.

The melting point was 85-87·co, the yield was 1.7z, and the yield was 79.1%.

IR(KBr-vcrn'); 3440.31
60.2950.1718 1680.1500.14
60.1390.1365.1190.1100.80
0° Elemental analysis result CHN Analysis value (%) 72.83 8.50 5.78 Calculated value (%) 72.87 8.50 5.67 (C15
H21N02) Example 4 2-(4'-isobutylphenyl)propionic acid (n)
In the same reaction flask as described in Example 1, 2f (0,008 mol) of 2-ace)-2-(4'-isobutylphenyl)propionamide (I) obtained in Example 3 and 401 rLl of glacial acetic acid were added. and stirred to dissolve.

Next, 49 mA' of concentrated hydrochloric acid was added dropwise at 100 to 105°C over 1 hour, and the mixture was further stirred at 100 to 105°C for 3 hours.

Most of the acetic acid was recovered from this reaction solution by distillation under reduced pressure.

The residue was drained into 50 liters of water and extracted with benzene.

The benzene layer was sufficiently stirred with a 2% aqueous sodium carbonate solution 401 and then separated, and the sodium carbonate solution layer was made acidic with dilute hydrochloric acid to precipitate 2-(4'-inbutylphenyl)propionic acid (I[).

It was filtered for 1 hour and recrystallized from n-hexane.

Yield 1.41°, melting point 74-75.5°C.

Yield 83.4% [vs. 2-aceto-2(4'-inbutylphenyl)propionitrile] IR (KBr -vcr
n');2950.3000~2400.172
0.1380.1230°780° Example 5 Sodium salt of 2-ace)-2-(4'-inbutylphenyl)acetonitrile (IV) and 2-aceto-2
-(4'-isobutylphenyl)propionitrile (I
Preparation of II) In the same reaction flask as described in Example 1, ethyl alcohol 1507711, metallic sodium 9. (1(0,39
A small piece of 1 mol) was added and warmed to dissolve.

In this, 4-isobutylphenylacetonitrile (see reference side) 50P (0,289 mol) and ethyl acetate 4
A mixed solution of 5P (0,511 mol) was added from a separatory funnel to
The dropwise addition took 1 hour at 75°C.

Near the end of the dropwise addition, a large amount of sodium salt of 2-ace)-2-(4'-inbutylphenyl)acetonitrile (IV) crystallized and precipitated.

After further stirring at 70°C for 2 hours, the mixture was sufficiently cooled and the crystals were filtered and washed several times with 10rrLl of cold ethyl alcohol.

It is then dried to form a colorless crystalline powder of 2-aceto2-
(4'-isobutylphenyl)acetonitrile (IV)
The sodium salt of was obtained.

Yield: 52.0 y0 Yield: 76.0% [based on 4-isobutylphenylnitrile] The melting point of this product was 230°C or higher.

Even when left in the atmosphere, there was no tendency for moisture absorption and deliquescence, and the product was stable and easily soluble in water, and could be recrystallized from dilute alcohol.

The measured values of the infrared absorption spectrum are as follows, and the absorption band (770-735 cI) peculiar to the ortho-substituted phenyl nucleus
rL-1) showed no absorption at all.

IR (KBr, vcrfL'): 3600~3
000°2960~2850.21701159015
20.1485.1420.1300980.855.
807゜Elemental analysis result HNNa Analysis value (%) 70.82 6.83 5.86 9
．． 92 words and customs (%) 70.87 6.79
5.90 9.68 (C14Hl a N0Na
(Measurement calculation with Na as ash content NaO) Next, the sodium salt 2 of 2-ace)-2-(4'-isobutylphenyl)acetonitrile (IV) obtained above
(1 (0,084 mol), isopropyl alcohol 70
m1 and dimethylformamide 5M were placed in the reaction flask and dissolved.

Methyl iodide 15f (0.105 mol) was gradually added dropwise from a separatory funnel and stirred.

During this time, the contents were kept at 10-15°C.

After stirring at the same temperature for 2 hours, gradually raise the temperature to 40-40
The reaction was completed by stirring at 5°C for 3 hours.

After recovering the solvent, it was drained into the remaining water (20QmA'), and the separated oil was extracted with benzene, washed with water, and dried over anhydrous sulfur salt.

Benzene was distilled and recovered, and the residue was distilled under reduced pressure.

2-aceto2-(4'-iso7''f-ruphenyl)furopionitrile (III) was obtained as a fraction with a boiling point of 122-125.0°C/1.5 degrees Hg.

Yield 13. OS'0 yield 72.6% (vs. 2-ace)-2
-(4'-isobutylphenyl)acetonitrile sodium salt].

Reference Example 4 - Production of isobutylbenzyl chloride and 4-isobutylphenylacetonitrile (V) Isophylbenzene 70f (0,522 mol) Niparaformaldehyde 23.1S' (0,770 mol), glacial acetic acid 70rfLl and anhydrous zinc chloride 35S ' was placed in a reaction flask and stirred at 40'C for 5 hours while blowing in hydrochloric acid gas.

The reaction product was discharged into 300 TfLl of water, and the oil was separated.
Wash with water and dilute aqueous sodium carbonate solution, dry with anhydrous salt water, and distill under reduced pressure to obtain a boiling point of 125-132℃/20
4-isobutylbenzyl chloride of mmHg abso was obtained.

Yield 61.5f.

Yield 82.3% (based on consumed imprutilbenzene).

The recovery rate of unreacted isobutylbenzene was 13.69.

The fraction was analyzed by GC (10% silicon 5E-30, packed with Celite 545, 5 m x 3 rIt11 L, carrier gas He, Inj.

280℃, Det, 200℃, TCD, Shimadzu 4APTF
)・As a result, it contained 9.5% ortho form.

IR; (Liquid film νcrfL-1); 3000-2800.
1500.1460.1380.1365.1280.
8401750.660° Next, 60 Tll of dimethyl sulfoxide and 15 f (0,306 mol) of sodium hydroxide were charged into the reaction flask.

To this, 4-isobutylbenzyl chloride 5 obtained above
M'(0,274-E-#) was added dropwise at 30 to 35°C over 1 hour and stirred.

The reaction was completed by stirring at 35-40°C for 2 hours.

The reactant was discharged into 300a of water, the oil was taken up in benzene, washed with water, dried, and then distilled under reduced pressure to a boiling point of 115-120℃/
4-isobutylacetonitrile was obtained as a fraction of 2.5 mmHg abso.

Yield: 42.9P, yield: 90.5% (based on 4-isobutylbenzyl chloride).

As a result of GC analysis (see above), the fraction contained 9.0% ortho form.

■R; (of liquid film ν ); 3040~2800° 2250° 1515. 14.60° 1460° 1390° 1370. 1170. 1120. 920, 401 795. 760°

Claims (1)

[Scope of Claims] 1. 2-(4/ - A method for producing isobutylphenyl)propionic acid. 2-Ace)-2-(4/-inbutylphenyl)propionitrile represented by formula (DI) is hydrolyzed to produce 2-ace)-2-(4'-isobutylphenyl) represented by formula (). ) A method for producing 2-(4/-ipionic acid represented by formula (I)), which comprises obtaining propionamide and hydrolyzing the same. -Ace)-2-(4'-isobutylphenyl)acetonitrile is reacted with a methylating agent to obtain 2-aceto-2-(4'-isobutylphenyl)propionitrile represented by formula (m). After hydrolysis, the formula (
2-(4/-isobutylphenyl) represented by formula (n), which is characterized by obtaining 2-ace)-2-(4'-isobutylphenyl)propionamide represented by I) and hydrolyzing it. Method for producing fropionic acid. 4 4-isobutylphenylacetonitrile represented by formula (V) is reacted with acetic acid ester to obtain 2-ace)-2-(4'-isobutylphenyl)acetonitrile represented by formula (IV), and a methylating agent is added to this. was reacted to obtain 2-aceto-2-(4'-isobutylphenyl)propionitrile represented by the formula (m), which was then hydrolyzed to form the formula (
2(4/-isobutylphenyl) represented by formula (I[), which is characterized by obtaining 2-ace)-2-(4'-isobutylphenyl)propionamide represented by formula (I) and hydrolyzing it. Method for producing propionic acid.